The purpose of this exploratory-developmental (R21) research grant proposal is to investigate whether loss of E-cadherin in basal keratinocytes and their progeny is facilitative in the development of ultraviolet (UV) lightinduced skin squamous cell carcinomas (SCCs) and examine the mechanism(s) by which UV radiation induces E-cadherin down-regulation. Our preliminary data demonstrate that chronic UV-irradiation in SKH-1 hairless mice results in a statistically significant reduction of E-cadherin expression as lesions progress from early in situ carcinomas with isolated areas of dysplasia, through small and large invasive SCCs. Therefore we hypothesize that loss of E-cadherin expression in basal keratinocytes is critical in the early development and subsequent progression of UV-induced skin cancers. In this proposal, we will first employ loss of function studies to determine in a temporally regulated and epidermal-specific fashion whether E-cadherin down-regulation facilitates SCC development. This will be done using our well established model of photocarcinogenesis that has previously been shown to mimic the development of skin carcinogenesis in humans. Second, we will explore whether [unreadable]-catenin mobilization, resulting from targeted E-cadherin deletion, induces alterations in keratinocytes by activating the TCF-LEF1 signaling pathway. Moreover, since we recently demonstrated that inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo or in vitro abrogated this UV-induced E-cadherin downregulation, we will also examine the mechanism by which PGE2-EP2 signaling induces this loss of cell surface E-cadherin. Since epithelial cancers comprise 80% of all human cancers, research that dissects how loss of cell surface E-cadherin facilitates neoplastic transformation in one epithelial system would likely be important in others. Moreover, in depth knowledge of how specific degradative pathways contribute to UV-induced E-cadherin downregulation might also provide new targets for anti-invasive therapy. Finally, the discovery of 'crosstalk'between the EP2 signaling pathway and these proteolytic pathways might yield new targets for validation in cancer diagnosis and therapy. PUBLIC HEALTH RELEVANCE: Since epithelial cancers comprise 80% of all human cancers, development of mouse model systems in which E-cadherin is selectively deleted in epithelium, may enhance our understanding of how early in situ lesions form and progress to SCCs after a repetitive UV injury. Moreover, in depth knowledge of how specific degradative pathways, via PGE2-EP2 signaling, contribute to UV-induced E-cadherin downregulation might yield new targets for validation in cancer diagnosis and therapy.